Does Loosening the Inclusion Criteria of the CROSS Trial Impact Outcomes in the Curative-Intent Trimodality Treatment of Oesophageal and Gastroesophageal Cancer Patients?

AIM: To determine the efficacy of preoperative chemoradiotherapy as per the CROSS protocol for oesophageal/gastroesophageal junction cancer (OEGEJC), when expanded to patients outside of the inclusion/exclusion criteria defined in the original clinical trial. MATERIALS AND METHODS: Data were collected retrospectively on 229 OEGEJC patients referred for curative-intent preoperative chemoradiotherapy. Outcomes including pathological complete response (pCR), overall survival (OS), cancer-specific survival and recurrence-free survival (RFS) of patients who met CROSS inclusion criteria (MIC) versus those who failed to meet criteria (FMIC) were determined. RESULTS: In total, 42.8% of patients MIC, whereas 57.2% FMIC; 16.6% of patients did not complete definitive surgery. The MIC cohort had higher rates of pCR, when compared with the FMIC cohort (33.3% versus 20.6%, P = 0.039). The MIC cohort had a better RFS, cancer-specific survival and OS compared with the FMIC cohort (P = 0.006, P = 0.004 and P = 0.009, respectively). Age >75 years and pretreatment weight loss >10% were not associated with a poorer RFS (P = 0.541 and 0.458, respectively). Compared with stage I-III patients, stage IVa was associated with a poorer RFS (hazard ratio (HR) = 2.158; 95% confidence interval (CI) = 1.339-3.480, P = 0.001). Tumours >8 cm in length or >5 cm in width had a trend towards worse RFS (HR = 2.060; 95% CI = 0.993-4.274, P = 0.052). CONCLUSION: Our study showed that the robust requirements of the CROSS trial may limit treatment for patients with potentially curable OEGEJC and can be adapted to include patients with a good performance status who are older than 75 years or have >10% pretreatment weight loss. However, the inclusion of patients with celiac nodal metastases or tumours >8 cm in length or >5 cm in width may be associated with poor outcomes.

Theoretical considerations in determining allometric growth within instars of crustaceans, with special reference to Americamysis bahia.

Allometry in crustaceans is typically considered growth over several instars primarily because crustaceans are presumed to grow only during ecdysis (discontinuous growth). Using theoretical distributions of the sizes of two morphometric variables over several instars, four theoretical instar allometry models are postulated: continuous allometry (indiscrete and discrete); discontinuous allometry (indiscrete and discrete); mixed allometry (simple or complex); and two-rate continuous allometry. The estimates of proportions of allometry within the instars are determined using Y = f(X) and X = f(Y) for variables X and Y. The amount of allometry in each variable is estimated using the mean ± standard deviation on the independent variable. Application of these theoretical instar allometry models using carapace and abdomen sizes in six instars indicates Americamysis bahia experiences two-rate continuous allometry, rather than "traditional" discontinuous allometry, with 85% or more of total growth occurring in the intermolt phase, and with the abdomen accounting for about 60% of the expansion.

Expression of dihydropyrimidine dehydrogenase (DPD) and hENT1 predicts survival in pancreatic cancer.

BACKGROUND: Dihydropyrimidine dehydrogenase (DPD) tumour expression may provide added value to human equilibrative nucleoside transporter-1 (hENT1) tumour expression in predicting survival following pyrimidine-based adjuvant chemotherapy. METHODS: DPD and hENT1 immunohistochemistry and scoring was completed on tumour cores from 238 patients with pancreatic cancer in the ESPAC-3(v2) trial, randomised to either postoperative gemcitabine or 5-fluorouracil/folinic acid (5FU/FA). RESULTS: DPD tumour expression was associated with reduced overall survival (hazard ratio, HR = 1.73 [95% confidence interval, CI = 1.21-2.49], p = 0.003). This was significant in the 5FU/FA arm (HR = 2.07 [95% CI = 1.22-3.53], p = 0.007), but not in the gemcitabine arm (HR = 1.47 [0.91-3.37], p = 0.119). High hENT1 tumour expression was associated with increased survival in gemcitabine treated (HR = 0.56 [0.38-0.82], p = 0.003) but not in 5FU/FA treated patients (HR = 1.19 [0.80-1.78], p = 0.390). In patients with low hENT1 tumour expression, high DPD tumour expression was associated with a worse median [95% CI] survival in the 5FU/FA arm (9.7 [5.3-30.4] vs 29.2 [19.5-41.9] months, p = 0.002) but not in the gemcitabine arm (14.0 [9.1-15.7] vs. 18.0 [7.6-15.3] months, p = 1.000). The interaction of treatment arm and DPD expression was not significant (p = 0.303), but the interaction of treatment arm and hENT1 expression was (p = 0.009). CONCLUSION: DPD tumour expression was a negative prognostic biomarker. Together with tumour expression of hENT1, DPD tumour expression defined patient subgroups that might benefit from either postoperative 5FU/FA or gemcitabine.

Intratumoural expression of deoxycytidylate deaminase or ribonuceotide reductase subunit M1 expression are not related to survival in patients with resected pancreatic cancer given adjuvant chemotherapy.

BACKGROUND: Deoxycytidylate deaminase (DCTD) and ribonucleotide reductase subunit M1 (RRM1) are potential prognostic and predictive biomarkers for pyrimidine-based chemotherapy in pancreatic adenocarcinoma. METHODS: Immunohistochemical staining of DCTD and RRM1 was performed on tissue microarrays representing tumour samples from 303 patients in European Study Group for Pancreatic Cancer (ESPAC)-randomised adjuvant trials following pancreatic resection, 272 of whom had received gemcitabine or 5-fluorouracil with folinic acid in ESPAC-3(v2), and 31 patients from the combined ESPAC-3(v1) and ESPAC-1 post-operative pure observational groups. RESULTS: Neither log-rank testing on dichotomised strata or Cox proportional hazard regression showed any relationship of DCTD or RRM1 expression levels to survival overall or by treatment group. CONCLUSIONS: Expression of either DCTD or RRM1 was not prognostic or predictive in patients with pancreatic adenocarcinoma who had had post-operative chemotherapy with either gemcitabine or 5-fluorouracil with folinic acid.

Adherence to treatment guidelines in stage II/III rectal cancer in Alberta, Canada.

AIMS: Evidence suggests that pre- and/or postoperative treatment benefits patients with stage II/III rectal cancer. This study aimed to quantify treatment patterns and adherence to treatment guidelines, and to identify barriers to having a consultation with an oncologist and barriers to receiving treatment in stage II/III rectal cancer, in a publicly funded medical care system. MATERIALS AND METHODS: Patients with surgically treated stage II/III rectal adenocarcinoma, diagnosed from 2002 to 2005 in Alberta, a Canadian province with a population of 3 million, were included. Demographic and treatment information from the Alberta Cancer Registry were linked to data from electronic medical records, hospital discharge data and the 2001 Canadian Census. The study outcomes were 'not having an oncologist consultation' and 'not receiving guideline-based treatment'. The relative risks of the two outcomes in association with patient characteristics were estimated using multivariable log-binomial regression. RESULTS: Of a total of 910 surgically treated stage II/III rectal adenocarcinoma patients, 748 (82%) had a consultation with an oncologist and 414 (45.5%) received treatment. Pre-/post-surgical treatment modalities and timing varied; 96 (10.5%) received neoadjuvant treatment only, 389 (42.7%) received adjuvant treatment only, 119 (13.1%) received both, and 306 (33.6%) had surgery alone. Factors related to not having a consultation with an oncologist included older age, co-morbidities, cancer stage II and region of residence. Older age was the most significantly associated factor with not receiving treatment (relative risk=2.23; 95% confidence interval: 1.89, 2.64). CONCLUSIONS: Disparities exist in the receipt of treatment in stage II/III rectal cancer. Factors such as age, region of residence and stage should not be barriers to consulting an oncologist to discuss or receive treatment. The reasons for these disparities need to be identified and addressed.

Utilization of oncology services and receipt of treatment: a comparison between patients with breast, colon, rectal, or lung cancer.

BACKGROUND: Higher awareness could translate into better care for patients with breast cancer than for those with other cancers. This study examines utilization of two key oncology services across cancer sites: consultation with an oncologist and receipt of treatment. PATIENTS AND METHODS: All residents of Alberta, Canada, who were diagnosed in 2005 with breast, colon, rectal, or lung cancer and had a disease stage that should be treated with chemotherapy, radiation therapy, or hormonal therapy were included. Data were obtained from the Alberta Cancer Registry and electronic cancer medical records. Percentages of patients who had a consultation and who received treatment were compared. Multivariable log-binomial regression models were used to identify patient characteristics associated with not having the outcomes. RESULTS: A much higher percentage of patients with breast cancer had consultations and received treatment (92% and 83%, respectively) than those with colon (83% and 59%), rectal (86% and 73%), or lung (77% and 66%) cancer. Age, disease stage, region of residence, and surgery status are related to having a consultation and/or receiving treatment but the relationship varies by cancer site. CONCLUSION: Efforts are needed to eliminate disparities in utilization of key cancer services across cancer sites.

National biosecurity approaches, plans and programmes in response to diseases in farmed aquatic animals: evolution, effectiveness and the way forward.

The rapid increase in aquaculture production and trade, and increased attention to the negative effects of disease, are becoming stimuli for developing national biosecurity strategies for farmed fisheries, for which the World Organisation for Animal Health (OIE) Aquatic Animal Health Code and Manual of Diagnostic Tests for Aquatic Animals serve as an excellent framework. Using examples from a few countries and selected diseases, this paper provides a general overview of the development of approaches to implementing biosecurity strategies, including those emerging in the national legislation and regulations of some countries, and those being initiated by industries themselves. The determination of disease status in different epidemiological units (from a farm to a nation), appropriate approaches for preventing the introduction of disease and developing contingencies for disease control and eradication are also discussed. Important to the effectiveness of such strategies are provision of financial, personnel and other resources to implement them, including incentives such as indemnification or compensation in eradication programmes, and practical linkage to regulatory or government policy initiatives.

Refinement and use of Certificates of Veterinary Inspection (Health Certificates) for optimal assurance of disease freedom in aquatic animals.

Certificates of Veterinary Inspection (CVI), generally termed "Health Certificates", are pivotal for ensuring that translocated animals are not diseased or do not harbour significant pathogens. While used very successfully with terrestrial animal movement for decades, CVIs for aquatic animals are not well refined, understood or used, despite the availability of several aquatic animal "certification processes", "permits" and "health certificates", including the OIE model health certificates. Correctly designed CVIs provide the single most economical and effective assurance of disease status (generally freedom from specific diseases or pathogens) for individuals or lots of animals, at any point in time. When issued by a qualified independent third-party (typically a licensed and government accredited veterinarian) they provide the official level of assurance necessary for intrastate, interstate and international trade. Tailored modifications of CVIs are also useful for other purposes requiring the evaluation of animal health (e.g. specific pathogen-free (SPF) assurance for premises, risk-mitigating assurance necessary for insurance policies, breeding soundness assurance of broodstock, etc.). Here we discuss necessary information for aquatic animal CVIs: animal, ownership and location; standardized diagnostic results and their interpretation; and language contained in CVIs. Also addressed is the viability for use with multiple aquatic species and diseases/pathogens of interest, and their use in conjunction with established veterinary inspection procedures. A revised model aquatic CVI, with broad potential use for individual operations, states or countries, is offered for discussion, comment and refinement. In addition an optimally designed model CVI may be of use with electronic systems that are evolving in, for example, Europe, the USA and Australia/New Zealand (e.g. TRACES, e-CVI, e-Certs).

Science-based assessment of welfare: aquatic animals.

Terrestrial animal welfare has been a matter for exploration for many years. In contrast, approaches towards improving the welfare and humane treatment of aquatic animals are relatively new, as is the thinking behind them. Several issues complicate the process of addressing the welfare of aquatic animals in a consistent manner. These include the following: - the huge diversity among aquatic animals, the majority of which are poikilothermic vertebrates and invertebrates - understanding the practices involved in fisheries, aquaculture and aquatic animal production, and their purpose - the relative paucity of scientific information - understanding the philosophical approaches, policies, guidance and regulations that may influence the provision of optimal welfare and humane practices for aquatic animals. In this paper, the authors attempt to provide an overview of all these elements, relating what is known and understood about these issues for the primary group used in aquaculture and fisheries, finfish, and exploring the factors that may influence the concepts and practices of aquatic animal welfare. These factors seem to be the foundation of all welfare approaches and include: - ethical and moral concepts of animal welfare and humane treatment - whether animals experience suffering from the potentially adverse practices used in their maintenance, management and use - the public and institutional understandings of these issues and their results. These are discussed with the hope that future developments in, and approaches to, aquatic animal welfare will be of use to society, industries and the public.

Integration of palliative care with alternative medicine in patients who have refused curative cancer therapy: a report of two cases.

This article describes two young, potentially curable patients who chose a course of treatment that ultimately resulted in death. Their choice was in part influenced by the prospect of the disfiguring surgery that would have been required for cure. In the first patient this would have meant massive head and neck surgery, in the second, a radical hysterectomy that would have resulted in surgical menopause. The availability of practitioners who promised an easier cure was also a factor in swaying the first patient away from truly curative therapy. Denial also played a role in both of these patients' decisions. Part of their denial may have been exacerbated by the fact that both of their cancers have as risk factors behaviors that the patients may have considered inconsistent with their value system. In the first type of cancer, alcohol and chewing tobacco are major risk factors (11), neither of which would have been acceptable to the patient's family. In the second type, multiple sexual partners are a major risk for cervical cancer (12), a behavior which is inconsistent with the teachings of the patient's fundamentalist Christian beliefs. The approach that we have described--expressions of respect for the patient's belief system combined with the nonconfrontational offering of treatments with immediate symptomatic benefit--resulted in the development of an effective working relationship between patient, family, and palliative care team.

Luteinizing hormone and progesterone concentrations and induction of estrus after use of norgestomet ear implants or constant infusion of gonadotropin-releasing hormone in anestrous, nonlactating dairy goats.

Plasma luteinizing hormone and progesterone concentrations, time to onset of estrus, and pregnancy rates were determined in nonlactating anestrous does given 1 of 4 treatments: subcutaneous ear implants containing 3 mg of norgestomet for 9 days (NOR; n = 6); subcutaneous administration, using osmotic minipumps, of 250 ng of gonadotropin-releasing hormone (GnRH)/h for 48 hours (GnRH; n = 6); 3 mg of NOR for 9 days, followed immediately by 250 ng of GnRH/h for 48 hours (NOR + GnRH; n = 6); or no treatment (control; n = 6). During the 72-hour period after removal of NOR or insertion of GnRH pumps, 6 of 6, 0 of 6, 6 of 6, and 3 of 6 does were observed in estrus at a mean (+/- 13.8) hours in groups NOR, GnRH, NOR + GnRH, and control, respectively. Time from end of treatment to peak concentrations of luteinizing hormone were 56 +/- 4.0, 28 +/- 4.7, 34 +/- 4.3, and 41 +/- 9.7 hours (mean +/- SE) for NOR, GnRH, NOR +/- GnRH, and control, respectively. Peak concentrations of luteinizing hormone were significantly greater and occurred significantly later in does given NOR. Progesterone concentrations in does that became pregnant increased to concentrations greater than or equal to 1.0 ng/ml 3 to 5 days after breeding and remained high. Functional corpora lutea (CL) was found in 6 does that did not become pregnant, 1 CL was associated with pseudopregnancy and 1 CL was associated with ovulation prior to placement of the GnRH pumps. Functional CL failed to form in 10 of the 12 doses in groups GnRH and control.(ABSTRACT TRUNCATED AT 250 WORDS)

The toxin kainic acid: a study of avian nerve and glial cell response utilizing tritiated kainic acid and electron microscopic autoradiography.

Three questions are asked regarding the toxin kainic acid (KA). Does it destroy specific glial cells as well as neurons? Does KA gain access to the cytoplasm in intact cells and to which organelles does it bind? Intracerebral injections of tritiated KA into the pigeon (Columba livia) paleostriatal complex (basal ganglia) coupled with electron microscopic autoradiography revealed the following major points. Kainic acid destroyes oligodendrocytes, with pathophysiology apparent by 30 min after challenge with KA leading to cell destruction by 4 h. The response of astrocytes at the longest observation period (4 h) involves swelling of perivascular endfeet and processes in the neuropil. Reactive microglial-like cells show an accumulation of label in their cytoplasm, but no apparent morphological changes. The label appears in the cytoplasm of intact cells, both glia and neurons early after challenge with the toxin. Label is associated (bound) with mitochondria at an incidence significantly above chance at 30 min, 2 and 4 h after challenge with KA. Two hours after exposure to KA is the critical period where metabolic, physiological and morphological changes occur that lead to cell death. Cell destruction may be a consequence of KA-induced energy depletion. Kainate may interfere with adequate energy production by uncoupling glycolysis and the Krebs cycle in the mitochondria.

L-pyroglutamate: an alternate neurotoxin for a rodent model of Huntington's disease.

Intrastriatal injections of L-Pyroglutamate (L-PGA) in mice produced behavioral and neuropathological effects that resemble in part the kainate-injected rat striatal model of Huntington's Disease (HD). The behavioral responses induced after unilateral injections of L-PGA included circling, postural asymmetry of head and trunk and possible dyskinesias. The neuropil in the injected striatum contained dilated profiles, degenerating neurons and oligodendroglia, and numerous phagocytic microglial-like cells. A dose response relation existed. The size of the lesion (expressed as a percent volume of the striatum destroyed) ranged from 1 +/- 0.18% at 0.02 mumoles to 20.2 +/- 3.97% at 200 mumoles L-PGA (pH = 7.3). L-PGA is a weak neurotoxin when compared to kainic acid. Several factors raise interest in the possible role of L-PGA in HD, including the recently reported elevated plasma levels of L-PGA in some HD patients, and these considered in the discussion.